2-amino-6-halogenopurine is known as a useful intermediate for producing guanine nucleoside analogues, as described in Japanese Patent Examined Publication No. 33396/1981, Japanese Patent Laid-Open Nos. 58982/1985, 208954/1985, 59583/1990, 108788/1992 and other publications.
For synthesizing such a 2-amino-6-halogenopurine, some methods have already been developed. Methods for forming a 6-chloro derivative include a method wherein guanine is reacted with phosphorus pentasulfide to introduce a mercapto group to the 6-position of the purine ring, followed by chlorine sparging, to give a 6-chloro derivative (method 1) (British Patent No. 767,216; J. Am. Chem. Soc. 77, 1676). However, in this method, the decomposition product of the phosphorus pentasulfide used generates a strong odor so that there is a fear for environmental pollution. Also, the yield is unsatisfactory, and this compound is dangerous in that the resulting thioguanine is mutagenic. Another method wherein 2-amino-6-mercaptopurine is reacted with methyl iodide to give a 6-methylthio derivative, followed by chlorine sparging, to give a 6-chloro derivative has been known (method 2) (J. Am. Chem. Soc. 79, 2185-2188; J. Am. Chem. Soc. 82, 2633-2640), but this method also involves the same risk as described in the method 1, because it also uses thioguanine as a starting material.
Still another method wherein guanine is reacted with phosphorus oxychloride in the presence of a quaternary ammonium salt to directly synthesize a 6-chloro derivative has been reported (method 3) (Japanese Patent Laid-Open No. 227583/1986). However, this method is not economically advantageous because the quaternary ammonium salt is expensive and the yield is as low as 30 to 42% due to the poor solubility of guanine.
Methods for forming a 6-bromo derivative include a method wherein thioguanine is reacted with bromine to give a 6-bromo derivative (J. Org. Chem., 27, 986, 1962); and methods for forming a 6-iodo derivative include a method wherein thioguanine is reacted with chlorine to give a 6-chloro derivative, which is then reacted with hydrogen iodide to yield an iodo derivative (J. Pharm. Sci., 57, 2056, 1968). However, all these methods can cause environmental pollution because of the strong odor of the decomposition product of the phosphorus pentasulfide used to produce the starting material thioguanine as above, and they are not economically advantageous in that the overall yield involving the desired product 2-amino-6-halogenopurine is low and operation is troublesome.